This invention relates to soluble hydrophilic polymer suitable for medical use and as blood plasma substitutes and to a process for making the same.
Various substitutes for blood plasma consisting of dilute solutions of hydrophilic polymers either natural, such as dextran or gelatin, or synthetic, such as polyvinylpyrrolidone are known.
The molecular weight of such polymers is one of the most important characteristics of supplementary infusion solutions of such polymers used for clinical purposes. The molecular weight influences the elimination of the infusion solution from the blood circulation, its elimination by urine, its retention in the organism, in which the solution is used, sedimentation of erythrocytes and toxicity as well as the immunological properties. In addition, the shape of molecule has important effects also.
Molecular polydispersity, that is, dispersion of the high molecular weight material, such as by degradation to lower weight portions, remains the main problem. Products containing rather large high molecular weight fractions are generally biologically unfavorable. However, rather small molecules escape rapidly from the blood circulation system and, therefore, are inefficient. It has been found in the study of colloidal infusion solutions which were formerly used, that they are detained in RES, that is, in the reticulo-endothelial system of adrenal glands, milt and lungs, the cells of the liver parenchyma, the epithelium of the coiled channels of the kidney and numerous other organs and tissues, such as tissues in lungs, pancreas, brain, skin, muscles etc. The results found differed according to the molecular weight values.
To enable substantially perfect and complete elimination of synthetic polymers from an organism, a definite region of molecular weights has to be maintained, since higher molecular weights bring about the danger of retention in the organism and blocking of the RES. It is difficult to reach and maintain this accurate molecular weight region in large-scale industrial production. Therefore, it is advantageous to use molecules which are split in the organism. Such molecules or compounds have a good osmotic effect in clinical application and increase to a fair extent the amount of circulating liquid and ameliorate the critical state of a patient. After the molecules have been split, their molecular weight is low enough, so that they penetrate the kidneys by filtration without difficulty and are not detained in the blood circulation system or deposited in the RES.
A disadvantage of gelatin, either high molecular weight or partially degraded material, is its low stability in the organism because it is readily split by enzymes so far as to form amino acids which are both metabolized and easily separated from the organism. In addition, preparations made from degraded gelatin combining it into larger molecules by means of diisocyanates possess this disadvantage also since the urea bridges between individual peptide molecules cannot protect the peptide bonds from cleavage, even though they are split at a slower rate than peptides per se. This is the reason that the properties of plasma substitutes of the gelatin type change relatively quickly and are optimal only in the beginning, immediately after infusion.
Quite the reverse effect occurs with common synthetic polymers. They are not split enzymatically at all and are accumulated in the organism causing injury of it. On the other hand, when the average degree of polymerization is decreased to the extent that the polymers are separated by the kidneys, the properties of the substitutes are not optimal in any respect. First of all, the colloidal osmotic pressure is too high, especially in the beginning, and it decreases only gradually as the polymer is removed from the body of the organism. This unfavorably influences the water content in intercellular spaces and cells.
There exists, therefore, a need to provide materials which do not exhibit the above mentioned disadvantages.